Less Invasive Ventilation Yields Fewer Complications in Infants

Action Points

Less invasive surfactant application (LISA) during CPAP-assisted spontaneous breathing in very preterm infants did not significantly improve the primary outcome of survival without bronchopulmonary dysplasia.

LISA, which provides surfactant application through a thin endotracheal catheter, did improve survival without major complications.

Premature infants in respiratory distress receiving a less invasive form of artificial ventilation were no more likely to survive than intubated infants, but were less likely to experience major complications, according to the results of a small randomized controlled trial in Germany.

A greater portion of infants treated with less invasive surfactant application protocol (LISA, defined as a thin endotracheal catheter) during the administration of continuous positive airway pressure (CPAP) survived without bronchopulmonary dysplasia (67.3%) compared with infants who were immediately intubated (58.7%), but absolute risk reduction was not statistically significant (8.6%, 95% CI -5.0 to 21.9, P=0.20), reported Angela Kribs, MD, of the University of Cologne in Germany, and colleagues.

However, when stratified by gestational age, more infants treated with LISA survived without major complications compared with the control group (50.5% vs. 35.6%, absolute risk reduction 14.9%, 95% CI 1.4-28.2, P=0.02), they wrote in JAMA Pediatrics.

The authors noted fewer incidences of cystic periventricular leukomalacia and retinopathy of prematurity requiring laser therapy in the LISA group, though neither of these results was statistically significant. The number needed to treat was 6.7 (95% CI, 3.5-71.4), the authors wrote.

In addition, treatment failure occurred less often in the intervention group (47.1%) compared with the control group (57.7%), but length of stay was comparable (103 vs. 105 days, P=0.11).

Evaluating short-term safety and adverse events in the LISA group only, 56.1% of infants experienced desaturation and 11.2% had bradycardia. When implementing the protocol, the majority of applications were successful on the first try (72.9%).

In a separate audio interview, Kribs said that she thought this result would impact research in the neonatal field, because the investigators were able to prove infants survived without major neonatal complications when treated with LISA.

"I think the clinical impact may be that extremely and very preterm infants that can be stabilized with CPAP in the delivery room might [receive] surfactant with this less invasive form of surfactant application, and there is need for further research because it's not clear how it is possible to stabilize most babies without intubation in the delivery room," she said.

The Nonintubated Surfactant Application (NINSAPP) trial was a multicenter, randomized, clinical parallel-group study conducted in the neonatal intensive care units (NICUs) of 13 German hospitals from April 2009 to March 2012. Participants included spontaneously breathing infants ranging from 23.0 to 26.8 weeks of age who showed signs of respiratory distress syndrome (n=211). Overall, 107 were randomized to the LISA group and 104 to the control group. Clinical characteristics were similar in both groups.

In an accompanying editorial, Peter A. Dargaville, MBBS, of the University of Tasmania in Australia, called the results of this trial "praiseworthy" because it specifically examined premature infants. He added that while it added to the evidence accumulated by similar trials in favor of a less invasive method of treating infant respiratory distress, he pointed out that the trial measures short-term effects, and may miss more subtle complications.

"Although longer outcomes are likely to be reported from each of the three trials, none are powered to detect subtle differences in motor or cognitive impairments potentially arising from the period of desaturation and bradycardia that sometimes occurs during surfactant delivery in the untreated infant," he wrote.

Limitations noted by the authors include that the study was not blinded, that delay of extubation in the intervention group may have resulted in longer mechanical ventilation times, and that using a standard dose of surfactant regardless of infant weight may put higher-birthweight infants at a disadvantage.

Dargaville added that larger clinical trials were needed on the subject to study whether "short-term benefits are countered by any evidence of long-term harm."

Kribs said that she hoped additional studies might lead to more babies receiving these less invasive forms of treatment.

"We have to do further research about these first minutes to get information about possibilities to get the babies eligible to receive less invasive surfactant application," she said.

The authors concluded that "LISA is a promising new therapy for extremely preterm infants with respiratory distress syndrome, but it certainly deserves further investigation."

The study was supported by the University of Cologne and grants from the German Ministry of Research and Technology, the German Federal Ministry of Education and Research, and Koln Fortune.

Kribs has received speaking fees and travel grants from the surfactant-producing companies Abbott, Chiesi, and Lyomark.

Dargaville reported being chief investigator of the OPTIMIST-A trial investigating minimally invasive surfactant therapy, funded by the Royal Hobart Hospital Research Foundation and the Australian National Health and Medical Research Council, with in-kind support from Chiesi Farmaceutici. He also reported receiving lecture fees and consultancy compensation from AbbVie, Chiesi Farmaceutici, and Ikaria.

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